Some cancers - such as breast cancer - have a greater inheritable risk than others. Now, researchers from the Washington University School of Medicine in St. Louis, MO, shed light on why this is, paving the way for better genetic tests for cancer risk.

In a study published in Nature Communications, senior author Li Ding, PhD, of the McDonnell Genome Institute at Washington, and colleagues identified rare germline gene mutations across 12 cancer types that increase a person's likelihood of developing cancer. A germline is the genetic information that is inherited from both parents.

According to the researchers, previous genomic studies of cancer have compared sequencing data from patients' healthy tissue and tumor tissue in order to identify gene mutations that may play a role in cancer development.

That type of analysis, however, is unable to differentiate between inherited gene mutations present at birth and those that have developed over time. As such, Ding and colleagues set out to identify inherited gene mutations by assessing cells of patients that contain germline information.

The team searched for rare germline mutations in 114 genes known to play a role in cancer development.

The researchers explain that if a person possesses one copy of these genes from one parent that is mutated at birth, the healthy copy from the other parent is able to compensate for it. However, as these individuals age, they are are greater risk of developing mutations in the healthy copy of the gene, raising cancer risk.

"We looked for germline mutations in the tumor," says Ding. "But it was not enough for the mutations simply to be present; they needed to be enriched in the tumor - present at higher frequency. If a mutation is present in the germline and amplified in the tumor, there is a high likelihood it is playing a role in the cancer."

The researchers focused on pinpointing rare germline mutations called "truncations" because most genes with these mutations are completely disabled.

Germline mutations in BRCA genes identified in variety of cancers

Ding and colleagues identified rare germline truncations in all genes linked to the 12 cancer types, though they found such mutations were present at much higher levels in some cancers than others.

For example, 19% of ovarian cancer cases they analyzed had rare germline truncations, compared with only 4% of acute myeloid leukemia cases.

The team says they were surprised to find that these mutations were also present in 11% of stomach cancer cases - a rate that was similar to that of breast cancer cases, a cancer known to be highly heritable.

BRCA1 and BRCA2 genes - important for DNA repair - are well established for their role in breast cancer; together, mutations in the BRCA genes account for around 20-25% of all hereditary breast cancers.

However, in this study, the researchers identified a large number of germline truncations in BRCA1 and BRCA2 genes present in other cancers, including prostate cancer and stomach cancer.

"This suggests we should pay attention to the potential involvement of these two genes in other cancer types," says Ding. "Of the patients with BRCA1 truncations in the germline, 90% have this BRCA1 truncation enriched in the tumor, regardless of cancer type."

Six mutations of 'unknown clinical significance' disabled BRCA1 gene

Genetic testing is very useful for identifying women who may be at increased risk of breast cancer, enabling them to take action to lower their chances of developing the disease.

Such tests involve analyzing DNA in blood or saliva samples to identify mutations in BRCA1 and BRCA2 genes.

But Ding and colleagues note that these tests also uncover mutations that have "unknown clinical significance." As such, doctors are unable to determine whether these mutations affect genes in a way that may increase a person's risk of cancer.

In their study, the researchers analyzed 68 germline non-truncation mutations in the BRCA1 gene that have unknown clinical significance, and the team assessed how well the BRCA1 gene could perform a key DNA-repair function in the presence of each mutation.

They found that six of these mutations completely disabled the BRCA1 gene and were present at higher levels in tumors, suggesting such mutations may play a role in cancer development.

While Ding says their findings have identified these six mutations as "loss-of-function" genes, she says it is important to note that their study showed many more of these mutations with unknown clinical significance demonstrated no such effect.

"Many of these types of mutations are neutral, and we would like to identify them so that health care providers can better counsel their patients," says Ding.

Findings could improve genetic testing for cancer risk

While these findings need to be confirmed with further research, the team believes the results may open the door to improved genetic testing for cancer risk and the ability to use such testing to identify the risk of a broader range of cancer types.

Ding adds:

"In general, we have known that ovarian and breast cancers have a significant inherited component, and others, such as acute myeloid leukemia and lung cancer, have a much smaller inherited genetic contribution.

But this is the first time on a large scale that we've been able to pinpoint gene culprits or even the actual mutations responsible for cancer susceptibility."

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